Peloruside A (1), a 16-membered macrolide antitumor agent was first isolated by West and Northcote from the New Zealand marine sponge, Mycale hentscheli (West, L. M.; Northcote, P. T.; Battershill, C. N. J Org Chem 2000, 65, 445). It has shown potent antitumor activity against P388 murine leukemia cells with an IC50 value of 10 ng/mL. Peloruside A is a microtubule stabilizing agent and arrests cells in the G2-M phase (Hood, K. A.; West, L. M.; Rouwe, B.; Northcote, P. T.; Berridge, M. V.; Wakefield, S. J.; Miller, J. H. Cancer Res 2002, 62, 3356). However, like laulimalide, peloruside A binds to the non-taxoid site of tubulin and has shown to a synergistic effect with taxol (Pryor, D. E.; O'Brate, A.; Bilcer, G.; Diaz, J. F.; Wang, Y.; Wang, Y.; Kabaki, M.; Jung, M. K.; Andreu, J. M.; Ghosh, A. K.; Giannakakou, P.; Hamel, E. Biochemistry 2002, 41, 9109). The intriguing structure, very low natural abundance and important biology of peloruside A attracted immense interest in synthesis ((a) Paterson, I.; Di Francesco, M. E.; Kuhn, T. Org. Lett. 2003, 5, 599; (b) Ghosh, A. K.; Kim, J.-H. Tetrahedron Letters 2003, 44, 3967; (c) Ghosh, A. K.; Kim, J.-H. Tetrahedron Letters 2003, 44, 7659; (d) Liu, B.; Zhou, W. S. Org. Lett. 2004, 6, 71). Thus far, De Brabander et al. and subsequently Taylor and co-workers have achieved the total synthesis of peloruside A ((a) Liao, X.; Wu, Y.; De Brabander, J. K. Angew Chem Int Ed Engl 2003, 42, 1648; (b) Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303). Even so, additional synthetic procedures are useful to ensure the supply of peloruside A, and also to provide a route to analogs and derivatives of this important molecule.
Described herein is a process for forming a quaternary carbon, the process comprising the steps of; reacting a compound containing a 2-alkyl-2-ene-1-one moiety with a source of nucleophilic hydride; and adding a compound containing an aldehyde to form the quaternary carbon. The process may be used to prepare a wide variety of chemical compounds. In one illustrative embodiment, the process may be used for the preparation of a macrolactone such as, but not limited to, a peloruside, a mycalamide, a bryostatin, an epothilone, and the like.
Also described herein is a process for preparing a peloruside, including peloruside A and analogs and derivatives thereof. The process comprises the step of preparing an aldol intermediate that is subsequently converted into the peloruside. The compounds described herein are useful for treating a patient in need of relief from cancer, a cancer-related disease, or a disease linked to the presence of a population of pathogenic cells.